title: Filamin A protects cells against force-induced apoptosis by stabilizing talin- and vinculin-containing cell adhesions.
abstract: In mechanically loaded tissues such as weight-bearing joints, myocardium, and periodontal ligament, pathophysiological forces can disrupt cell-matrix contacts, which can induce cell death, leading to tissue and organ dysfunction. Protection against force-induced cell death may be mediated by filamin A (FLNa), an actin-binding protein that regulates β1 integrin-mediated cell adhesion. We examined the affect of filamin expression on collagen distribution and cell death in the periodontal ligament, a force-loaded tissue. Conditional deletion of FLNa in fibroblasts was associated with 2-fold increase of acellular areas in periodontal ligament and 7-fold higher proportions of apoptotic cells. In cultured fibroblasts with FLNa knockdown, we examined the affect of supraphysiological forces (1 pN/μm(2) cell area; applied through the β1 integrin) on recruitment of talin and vinculin to focal adhesions and on apoptosis. Compared with the wild type, FLNa-knockdown cells exhibited 3-fold increases in floating cells after overnight force application and a 2-fold increase in cell detachment. Force induced time-dependent reductions (P<0.05) in the numbers of activated β1 integrin-, talin-, and vinculin-stained adhesions in FLNa-knockdown compared with those in wild-type cells. We conclude that FLNa protects against apoptosis in force-loaded cells, and this protection is mediated by enhanced formation and maturation of matrix adhesions.
authors.affiliation: 1Room 244, Fitzgerald Building, 150 College St., University of Toronto, Toronto, ON, M5S 3E2, Canada. v.pinto@utoronto.ca.
authors.forename: Vanessa I
authors.initials: VI
authors.lastname: Pinto
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Senini
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Mwayi P
authors.initials: MP
authors.lastname: Kazembe
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology*; D016923:Cell Death; D064448:Filamins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013314:Stress, Mechanical; D016608:Talin / Q000378:metabolism*; D016596:Vinculin / Q000378:metabolism*
chemical_list: D064448:Filamins; D016608:Talin; D016596:Vinculin
keywords: anoikis; cell death; integrins; mechanoprotection; periodontal ligament